Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: Effects of ranolazine

BackgroundTimothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in CaV1.2 resulting in gain of function of the L-type calcium current (ICa,L). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome.ObjectiveThe purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of ICa,L and to examine the effects of ranolazine.MethodsAction potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 μM).ResultsBayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 ± 7 ms to 86.5 ± 25 ms). Stimulation at cycle lengths of 250–500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late INa were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 μM) suppressed all actions of BayK8644.ConclusionA left ventricular wedge model of long QT syndrome created by augmentation of ICa,L recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.